1. Field of the Invention
The present invention relates generally to antibodies to Huntington's disease protein as well as methods and means for making and using such antibodies.
2. Description of the Related Art
Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disorder that is caused by the extension of a polyglutamine (polyQ) tract in exon 1 the protein huntingtin (Htt) to a length of greater than 40 units (Reddy et al. Trends Neurosci. 22:248-255 (1999)). The huntingtin gene is known and the subject of U.S. Pat. No. 5,693,757. Mutant Htt with greater than 40 CAG repeats gains a toxic function and induces death in subpopulations of neurons in the striatum and cortex (Zoghbi et al. Annu. Rev. Neurosci. 23:217-247 (2000); Tobin et al. Trends Cell Biol. 10:531-536 (2000)). Neuronal death in HD has been attributed not only to polyQ toxicity, but also to activation of caspases, interference with transcriptional machinery, and sequestration/inactivation of wild-type Htt and other important cellular factors.
A hallmark of HD and other polyQ diseases is the formation of insoluble protein aggregates in affected neurons (Ross Neuron 19:1147-1150 (1997); Wanker Biol. Chem. 937-942 (2000). Immunohistochemistry and subcellular fractionation indicate that Htt is normally located in the cytoplasm while the mutant form of Htt is also found in aggregates in the nucleus (Ferrigno et al. Neuron 26:9-12 (2000)). A major component of the aggregates in HD is the N terminus exon 1 of mutant Htt. As normal huntingtin protein is localized in the cytoplasm and mutant huntingtin protein is found in aggregates, also known as and referred to as inclusions, in the nucleus (Ferrigno et al., Neuron, 26:9-12 (2000)), translocation of mutant huntingtin protein to the nucleus is believed to be important in the pathogenesis of HD.
Because there is no current treatment available for this disease, there is a clear need for new treatments for Huntington's disease. Molecules that block the toxic effects of Htt itself or the lethal consequences of its binding to other proteins have good potential for therapeutic use. Thus, antibodies may serve as treatments for Huntington's disease. An antibody termed 1C2 is described in WO 97/17445. Finkbeiner (U.S. Pat. No. 6,291,652) provides antibodies specific for proteins having polyglutamine expansions. In particular, Finkbeiner provides antibodies having a higher affinity than an antibody identified as 1C2.